NO792105L - PROCEDURES FOR THE PREPARATION OF N1-BENZOYL-N2-PHENYL-1,3-DIAMINOPROPAN-2-OLES - Google Patents

PROCEDURES FOR THE PREPARATION OF N1-BENZOYL-N2-PHENYL-1,3-DIAMINOPROPAN-2-OLES

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NO792105L
NO792105L NO792105A NO792105A NO792105L NO 792105 L NO792105 L NO 792105L NO 792105 A NO792105 A NO 792105A NO 792105 A NO792105 A NO 792105A NO 792105 L NO792105 L NO 792105L
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diaminopropan
hydroxy
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groups
compounds
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Hans Liepmann
Rolf Hueschens
Wolfgang Milkowski
Horst Zeugner
Henning Heinemann
Klaus-Ulrich Wolf
Insa Hell
Reinhard Hempel
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Kali Chemie Pharma Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Pyrrole Compounds (AREA)

Abstract

N1-benzoyl-N2-phenyl-1,3-diaminopropan-2-ols are disclosed which exhibit a stabilizing effect on the gastric mucosa and enhance the stability and resistance of the gastic mucosa against harmful effects caused by, e.g., excessive alcohol consumption or drugs. The compounds are useful in the prophylaxis and treatment of gastritis. Further disclosed are pharmaceutical compositions which are effective in stabilizing the gastric mucosa and in the treatment and proplylaxis of gastritis and which comprise as a pharmacologically active ingredient N1-benzoyl-N2-phenyl-1,3-diaminopropan-2-ols, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable diluent. Further disclosed are processes for the preparation of the N1-benzoyl-N2-phenyl-1,3-diaminopropan-2-ols.

Description

__F.r-emgangsmåte ved fremstilling au N^-benzoyl-^-fenyl-l i,3-diaminopropan-2-oler __F.r-method in the preparation of au N^-benzoyl-^-phenyl-1 i,3-diaminopropan-2-ols

Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av nye N1-benzoyl-N2~fenyl-1,3-diaminopropan-2-oler og deres farmasøytisk godtagbare salter. The present invention relates to a process for the production of new N1-benzoyl-N2~phenyl-1,3-diaminopropan-2-ols and their pharmaceutically acceptable salts.

N -benzoyl-N„-feny1-1,3-diaminopropan-2-olene kommer underThe N -benzoyl-N„-phenyl1-1,3-diaminopropan-2-ols come under

1<2>y\ 29- <" i' Oi1<2>y\ 29- <" i' Oi

den generelle formel II i DT-OS 2 221 558, men er ikke beskrevet der. Ifølge det nevnte patentskrift er de verdifulle mellom-produkter ved fremstilling av benzodiazepin- og benzodiazocin-derivater, som påvirker sentralnervesystemet og på grunn av deres egenskaper kan tjene som milde ataraxica , sedativer eller krampe-hemmende midler. En selvstendig farmakologisk virkning er ikke beskrevet for forbindelsene. the general formula II in DT-OS 2 221 558, but is not described there. According to the aforementioned patent, they are valuable intermediates in the production of benzodiazepine and benzodiazocine derivatives, which affect the central nervous system and, due to their properties, can serve as mild ataraxics, sedatives or anticonvulsants. An independent pharmacological effect has not been described for the compounds.

Det har overraskende vist seg at de nye N-^-benzoyl-^-fenyl-1,3-diaminopropan-2-oler med den generelle formel I har selvstendige verdifulle farmakologiske og terapeutiske egenskaper. De stabiliserer den gastro-intestinale slimhud mot forskjellige skadevirkninger og egner seg derfor for behandling av akutt og kronisk gastritis. It has surprisingly been shown that the new N-^-benzoyl-^-phenyl-1,3-diaminopropan-2-ols of the general formula I have independent valuable pharmacological and therapeutic properties. They stabilize the gastro-intestinal mucosa against various harmful effects and are therefore suitable for the treatment of acute and chronic gastritis.

,N1-benzoyl-N2-fenyl-1,3-diaminopropan-2-olene har formelen: ,N1-benzoyl-N2-phenyl-1,3-diaminopropan-2-ols have the formula:

hvor R1, R2og kan være like eller forskjellige, og er hydroxy, benzyloxy, klorbenzyloxy eller alkoxy med 1-4 carbonatomer, where R1, R2 and can be the same or different, and are hydroxy, benzyloxy, chlorobenzyloxy or alkoxy with 1-4 carbon atoms,

idet to nabogrupper kan danne en methylendioxy- eller ethylen-dioxygruppe, eller hvor to methoxygrupper kan være kombinert med where two neighboring groups can form a methylenedioxy or ethylenedioxy group, or where two methoxy groups can be combined with

en allyloxy-, propargyloxy-, acetoxy- eller alkoxycarbonyloxy-gruppe hvor alkoxygruppen maksimalt har to carbonatomer, R^er hydrogen, alkyl med 1-4 carbonatomer, (3-hydroxyethyl eller P-methoxyethyl, an allyloxy, propargyloxy, acetoxy or alkoxycarbonyloxy group where the alkoxy group has a maximum of two carbon atoms, R^ is hydrogen, alkyl with 1-4 carbon atoms, (3-hydroxyethyl or P-methoxyethyl,

R , R£og R^, som er like eller forskjellige, er hydrogen, halogen, alkyl med 1-4 carbonatomer, alkoxy med 1-4 carbonatomer, idet to nabogrupper kan danne en methylendioxy- eller ethylen-dioxygruppe, eller en av gruppene R ^, R^og R^er en trifluor-methyl- eller nitrogruppe, eller når R^ , R2 og R^sammen er 3>4>5-trimethoxy og R^ermethyl, er ikke mere enn to av substituentene R^, R^ og R^hydrogen, samt deres syreaddisjonssalter, R , R£ and R^, which are the same or different, are hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, two neighboring groups can form a methylenedioxy or ethylenedioxy group, or one of the groups R^, R^ and R^ are a trifluoromethyl or nitro group, or when R^, R2 and R^ together are 3>4>5-trimethoxy and R^ermethyl, no more than two of the substituents R^, R^ and R^hydrogen, as well as their acid addition salts,

og når i forbindelsene med den generelle formel I minst én av substituentene R , R og R er hydroxy, salter av disse forbind-eiser med farmakologisk godtagbare kationer. and when in the compounds of the general formula I at least one of the substituents R, R and R is hydroxy, salts of these compounds with pharmacologically acceptable cations.

Som alkylgrupper i alkyl- og alkoxygruppene med 1-4 carbonatomer kommer rettkjedede og forgrenede alkylgrupper på tale, som methyl, ethyl, propyl, isopropyl, n-butyl eller isobutyl. Som halogenatomer er fluor, klor, brom og jod egnet, særlig fluor, klor og brom. Alkyl groups in the alkyl and alkoxy groups with 1-4 carbon atoms include straight-chain and branched alkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl. As halogen atoms, fluorine, chlorine, bromine and iodine are suitable, especially fluorine, chlorine and bromine.

f f

Gjenstand for foreliggende oppfinnelse er fremgangsmåter ved fremstilling av forbindelsene med den generelle formel I. The subject of the present invention are methods for the preparation of the compounds of the general formula I.

De nye forbindelser fåes ved at manThe new connections are obtained by

a) omsetter en 1,3-diaminopropan-2-ol med formelen!a) reacts a 1,3-diaminopropan-2-ol with the formula!

hvor R^, R^, Rg ogR^er som ovenfor angitt, med et benzoylderivat where R^, R^, Rg and R^ are as above, with a benzoyl derivative

med formelen:with the formula:

hvor R R * og R ' er forethrede og/eller forestrede hydroxygrupper med den ovenfor nevnte betydning, og X er en reaksjonsdyktig syrerest, som halogen, en laveremolekylær alkoxygruppe eller 0-CO-Y, hvor Y er en laveremolekylær alkoxygruppe, eventuelt i et inert oppløsningsmiddel ved temperaturer mellom -10°C og kokepunktet for det anvendte oppløsningsmiddel ved normaltrykk eller under forhøyet trykk, til forbindelser med formel I hvor Rn, R_ og R„ er forethrede og/eller forestrede hydroxygrupper med den ovenfor angitte betydning, og R^, R^, R^ og R^ er som ovenfor angitt, b) én eller flere av substituentene R^, R o og R^med betydningen benzyloxy eller klorbenzyloxy spaltes eventuelt hydrogenolytisk til de tilsvarende hydroxygrupper, c) eventuelt overføres forbindelsene hvor substituentene R^ , R2eller R^er acetoxy eller alkoxycarbonyloxy ved alkalisk hydrolyse where R R * and R ' are etherified and/or esterified hydroxy groups with the above-mentioned meaning, and X is a reactive acid residue, such as halogen, a lower molecular alkoxy group or 0-CO-Y, where Y is a lower molecular alkoxy group, possibly in an inert solvent at temperatures between -10°C and the boiling point of the solvent used at normal pressure or under elevated pressure, to compounds of formula I where Rn, R_ and R„ are etherified and/or esterified hydroxy groups with the above meaning, and R^, R^, R^ and R^ are as stated above, b) one or more of the substituents R^, R o and R^ with the meaning benzyloxy or chlorobenzyloxy are optionally hydrogenolytically cleaved to the corresponding hydroxy groups, c) optionally the compounds are transferred where the substituents R^ , R 2 or R 1 is acetoxy or alkoxycarbonyloxy by alkaline hydrolysis

til de tilsvarende hydroxyforbindelser,to the corresponding hydroxy compounds,

d) eventuelt overføres én eller flere av substituentene R^ , R2 og R 3med betydningen hydroxy til de ønskede alkoxy-, allyloxy-, propargyloxy- eller til de eventuelt substituerte benzyloxygrupper med ovenstående betydning, e) eventuelt overføres R^med betydningen hydrogen til R^med betydningen alkyl, f) de isolerte frie baser av forbindelsene med formel I over-føres til deres syreaddisjonssalter eller de frie baser frigjøres d) optionally, one or more of the substituents R , R 2 and R 3 with the meaning hydroxy are transferred to the desired alkoxy, allyloxy, propargyloxy or to the optionally substituted benzyloxy groups with the above meaning, e) optionally, R 3 with the meaning hydrogen is transferred to R ^with the meaning alkyl, f) the isolated free bases of the compounds of formula I are transferred to their acid addition salts or the free bases are liberated

fra deres syreaddisjonssalter, ellerfrom their acid addition salts, or

g) eventuelt omsettes forbindelsene med formel I med farmakologisk godtagbare kationer til de tilsvarende metall-oxydoforbindelser, når minst én av substituentene R1, R2og R^ er hydroxy. g) the compounds of formula I are optionally reacted with pharmacologically acceptable cations to the corresponding metal oxydo compounds, when at least one of the substituents R1, R2 and R1 is hydroxy.

Fortrinnsvis utføres omsetningen av 1,3-diaminopropan-2-olene med formel II med benzoylderivatene med formel III i nærvær av et syrebindingsmiddel, som f.eks. kaliumcarbonat, nat rium-carbonat, natriumhydroxyd, kaliumhydroxyd, triethylamin eller pyridin. Anvendt i overskudd kan de tertiære aminer også tjene som inert oppløsningsmiddel. Som inerte oppløsningsmidler er f.eks. methylenklorid, kloroform, aceton, tetrahydrofuran, dioxan, benzen, toluen eller klorbenzen, egnet. Preferably, the reaction of the 1,3-diaminopropan-2-ols of formula II with the benzoyl derivatives of formula III is carried out in the presence of an acid binder, such as e.g. potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or pyridine. Used in excess, the tertiary amines can also serve as an inert solvent. As inert solvents are e.g. methylene chloride, chloroform, acetone, tetrahydrofuran, dioxane, benzene, toluene or chlorobenzene, suitable.

Ved fremstilling av N^benzo<y>l-T^-fen<y>l-l, 3-diaminopropan-2-olene med formel I, hvor én eller flere av substituentene R^, R^ 0 og R 3 er hydroxy, omsettes hensiktsmessig 1,3-diaminopropan-2-olene med formel II med benzoylderivatene med formel III i hvilke hydroxygruppen er forsynt med en beskyttelsesgruppe, som eksempelvis en benzyl-, acetyl- eller alkoxycarbonylgruppe, og senere avspaltes beskyttelsesgruppen. Dette lar seg gjøre ved at man f.eks. avspalter benzyloxygruppen hydrogenolytisk med hydrogen i nærvær av en edelmetallkatalysator, som f.eks. palladiumkull, ved temperaturer mellom 15° og 50°C. Som oppløsningsmiddel kan herved anvendes lavere alkoholer, dioxan, tetrahydrofuran eller ethylacetat. Ved spaltning av acetoxy- eller alkoxycarbonyloxy-gruppén kan en alkalisk hydrolyse med f.eks. natrium- eller kaliumhydroxyd eller vandig ammoniakkoppløsning ved temperaturer mellom 25°'og 80° C anvendes, idet man som oppløsningsmiddel anvender lavere alkoholer, eventuelt under inert gassatmosfære, som nitrogen eller hydrogen. In the preparation of the N^benzo<y>l-T^-phen<y>l-l, 3-diaminopropan-2-ols of formula I, where one or more of the substituents R^, R^ 0 and R 3 are hydroxy, suitably react 1 The ,3-diaminopropan-2-ols of formula II with the benzoyl derivatives of formula III in which the hydroxy group is provided with a protective group, such as for example a benzyl, acetyl or alkoxycarbonyl group, and later the protective group is removed. This can be done by e.g. cleaves off the benzyloxy group hydrogenolytically with hydrogen in the presence of a noble metal catalyst, such as e.g. palladium coal, at temperatures between 15° and 50°C. Lower alcohols, dioxane, tetrahydrofuran or ethyl acetate can be used as solvents. When splitting the acetoxy or alkoxycarbonyloxy group, an alkaline hydrolysis with e.g. sodium or potassium hydroxide or aqueous ammonia solution at temperatures between 25° and 80° C are used, lower alcohols being used as solvents, possibly under an inert gas atmosphere, such as nitrogen or hydrogen.

Av de således erholdte -hydroxybenzoyl -^-f enyl -1, 3-diaminopropan-2-oler med'formel I kan man eventuelt også frem-stille forbindelsene med formel I som har ethergrupper på benzoyl-gruppen, idet man omsetter alkalisaltene av -hydroxybenzoyl-forbindelsene i nærvær av lavere alkoholer ved 30° til 100°C med et halogenalkan, halogenalken, halogenalkyn eller halogenbenzyl, eventuelt i et lukket kar under beskyttelsesatmosfære. From the -hydroxybenzoyl -^-phenyl -1, 3-diaminopropan-2-ols of formula I thus obtained, the compounds of formula I which have ether groups on the benzoyl group can optionally also be prepared, by reacting the alkali salts of - the hydroxybenzoyl compounds in the presence of lower alcohols at 30° to 100°C with a haloalkane, haloalkene, haloalkyne or halobenzyl, optionally in a closed vessel under a protective atmosphere.

Fremgangsmåteforbindelsene med formel I hvor R^er hydrogen, kan ved efterfølgende alkylering på i og for seg kjent vis over-føres til de tilsvarende N-alkylforbindelser, særlig N-methyl-eller N-ethylforbindelser. Dette skjer f.eks. ved den fra littera-turen kjente fremgangsmåte ved reduktiv carbonyl-aminering som Leuckart-Wallach- hhv. Eschweiler-reaksjonene (se H. Krauch, The process compounds of formula I where R 1 is hydrogen can be transferred by subsequent alkylation in a manner known per se to the corresponding N-alkyl compounds, especially N-methyl or N-ethyl compounds. This happens e.g. by the method known from the literature by reductive carbonyl amination such as Leuckart-Wallach or The Eschweiler reactions (see H. Krauch,

W. Kunz, Reaktionen der Organischen Chemie (1976), s. 126 og 131) eller ved alkylering med dialkylsulfater (se Houben-Weyl, Xl/l W. Kunz, Reaktionen der Organischen Chemie (1976), pp. 126 and 131) or by alkylation with dialkyl sulfates (see Houben-Weyl, Xl/l

(1957), s. 207 ff). (1957), pp. 207 ff).

De fra reaksjonsblandingen isolerte frie baser med formel I kan eventuelt overføres til sine fysiologisk godtagbare syreaddisjonssalter ved i og for seg kjente metoder. Som egnede syrer har vist seg f.eks. saltsyre, hydrogenbromid, svovelsyre, salpetersyre, orthofosforsyre, cyclohexylaminosulfonsyre, amidosulfonsyre eller The free bases of formula I isolated from the reaction mixture can optionally be transferred to their physiologically acceptable acid addition salts by methods known per se. Suitable acids have proven to be e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, orthophosphoric acid, cyclohexylaminosulfonic acid, amidosulfonic acid or

p-toluensulfonsyre.p-toluenesulfonic acid.

Til de farmaskologisk godtagbare metall-oxydoforbindelser I kommer man når man f.eks. omsetter med alkali- eller jordalkali-alkoholater under en beskyttelsesatmosfære i nærvær av en lavere ' alkohol eller med et metallacetat, hhv. et metallsalt, som metall-klorid eller metallsulfat, i iseddik/vann ved temperaturer på 30 - 80°C. Som farmakologisk godtagbare metallsalter kan f.eks. nevnes de av natrium, magnesium, zink, kobber, aluminium eller vismut. The pharmacologically acceptable metal-oxydo compounds I are reached when, for example, reacts with alkali or alkaline earth alcoholates under a protective atmosphere in the presence of a lower alcohol or with a metal acetate, resp. a metal salt, such as metal chloride or metal sulfate, in glacial acetic acid/water at temperatures of 30 - 80°C. As pharmacologically acceptable metal salts, e.g. those of sodium, magnesium, zinc, copper, aluminum or bismuth are mentioned.

1,3_diaminopropan-2-olene med formel II kan fremstilles på den av M. Chadwick et al. i J. Med. Chem. 9, 874 (1966) beskrevne måte. The 1,3-diaminopropan-2-ols of formula II can be prepared on the basis of M. Chadwick et al. in J. Med. Chem. 9, 874 (1966) described manner.

Fremgangsmåteforbindelsene og deres salter oppviser nye farmakologiske virkninger. Av særlig interesse er deres evne til å stabilisere den gastro-intestinale ^limhud mot forskjellige skadevirkninger, som de opptrer f.eks. ved duodeno-gastrisk til-bakeløp, ved alkoholmisbruk eller som bivirkning i terapien med ikke-steroide antiflogistika såvel som steroider og kjemo-terapeutika. Problematikken ved en forstyrret slimbarriere er beskrevet f.eks. av W. F. Caspary i DMW 100 (1975), 1263-1268 og H. S. Murray et al. i Brit. Med. J. I, nr. 5896, s. 19-21 (1974). The process compounds and their salts exhibit new pharmacological effects. Of particular interest is their ability to stabilize the gastro-intestinal mucosa against various harmful effects, which they cause, e.g. with duodeno-gastric reflux, with alcohol abuse or as a side effect in therapy with non-steroidal antiphlogistics as well as steroids and chemo-therapeutics. The problem of a disturbed mucus barrier is described e.g. by W.F. Caspary in DMW 100 (1975), 1263-1268 and H.S. Murray et al. in Brit. With. J. I, No. 5896, pp. 19-21 (1974).

En kausal medikamentbehandling av disse lidelser er for tiden umulig. Der anvendes derfor symptomatisk antacida. A causal drug treatment of these disorders is currently impossible. Symptomatic antacids are therefore used.

Ved de spesielle farmakologiske egenskaper hos fremgangs-måt eforbindelsene muliggjøres for første gang en kausalterapi. Due to the special pharmacological properties of the process compounds, a causal therapy is made possible for the first time.

De egner seg for den kliniske anvendelse ved behandling av akutt og kronisk gastritis. They are suitable for clinical use in the treatment of acute and chronic gastritis.

Den ovennevnte virkning lar seg underbygge ved den efter-følgende farmakologiske prøve. The above-mentioned effect can be substantiated by the following pharmacological test.

Beskrivelse av de farmakologiske undersøkelsesmetoderDescription of the pharmacological investigation methods

I. Akutt toksisitetI. Acute toxicity

Den akutte 7-dagers toksisitet bestemmes efter en gangs administrasjon pr. os på hvite, fastende NMRI-mus. Beregningen av LD^0-verdien skjer over EDV ved en probitanalyse (L. Cavalli-Sforza, Gustav Fischer-Verlag, Stuttgart (1964), Grundbegriffe derBiometrie, s. 153 ff). The acute 7-day toxicity is determined after a single administration per os on white, fasted NMRI mice. The calculation of the LD^0 value takes place over EDV by a probit analysis (L. Cavalli-Sforza, Gustav Fischer-Verlag, Stuttgart (1964), Grundbegriffe derBiometrie, p. 153 ff).

2. Mavecelletap2. Stomach cell loss

Narkotiserte hanrotter av stammen SIV 50 behandles oralt med forsøksforbindelsen før begynnelsen av forsøket. Derpå administreres åcetylsalicylsyre som irritant for å frembringe et pato- Anesthetized male rats of the strain SIV 50 are orally treated with the test compound before the start of the experiment. Acetylsalicylic acid is then administered as an irritant to produce a patho-

logisk forhøyet epiteltap. For å bestemme det induserte total-celletap i rottemaven administreres åcetylsalicylsyre til dyrene uten forutgående administrasjon av beskyttelsesforbindelse. For preparering av dyrene for målingen blir trachea frilagt og logical elevated epithelial loss. To determine the induced total cell loss in the rat stomach, acetylsalicylic acid is administered to the animals without prior administration of protective compound. To prepare the animals for the measurement, the trachea is exposed and

intubert. Der skjer en laparotomi i medianen, fremtagelse av maven og innbinding av et venekateter for uttagelse av mavesaft. intubated. There is a laparotomy in the median, removal of the stomach and tying of a venous catheter for extraction of gastric juice.

Ved det innbundne kateter taes mavesaft ut, sentrifugeres og bedømmes mikroskopisk. With the tied catheter, gastric juice is taken out, centrifuged and assessed microscopically.

Den prosentuale nedsettelse av det av åcetylsalicylsyre forårsakede celletap ved forutgående administrasjon av 3 ganger 300 mg/kg av forsøksforbindelsen, bestemmes. The percentage reduction in cell loss caused by acetylsalicylic acid upon prior administration of 3 times 300 mg/kg of the test compound is determined.

Som forsøksforbindelse ble eksempelvis anvendt:For example, the following was used as a test compound:

A) N-L"(3 ,4,5-trimethoxybenzoyl) -Ng-methyl-N2-(4-f luorf enyl) - .1,3-diaminopropan-2-q,l B) N-j^- (3 ,4 ,5-trimethoxybenzoyl) -N2-methyl-N2- (4-klorf enyl) -1, 3-diaminopropan-2-ol C) N-^- (3 ,4 ,5-trimethoxybenzoyl) -N2-methyl-N2- (4~t rif luormethyl-fenyl)-1,3~diaminopropan-2-ol D) N-j^- (3 ,4 ,5-trimethoxybénzoyl) -N2-methyl-N2-(4-methylf enyl) -1 ,3-diaminopropan-2-ol E) N1-(3,4,5-trimethoxybenzoyl)-N2~ethyl-N2-(4-fluorfenyl)-1,3-diaminopropan-2-ol F) ^-(3,4 ,5-trimethoxybenzoyl) -n2~ (2 ,4 , 6-trimethylf enyl) -1, 3-diaminopropan-2-ol G) ^-(3,4,5-t riethoxybenzoyl)-N2-methyl-N2-(4-fluorfenyl)-1,3-diaminopropan-2-ol H) N!_(4-methoxy-2,3-ethylendioxybenzoyl)-N2~methyl-N2-(4-fluor-fenyl)-l,3-diaminopropan-2-ol A) N-L"(3 ,4,5-trimethoxybenzoyl)-N-methyl-N2-(4-fluorophenyl)-.1,3-diaminopropane-2-q,l B) N-j^- (3 ,4 , 5-trimethoxybenzoyl)-N2-methyl-N2-(4-chlorophenyl)-1,3-diaminopropan-2-ol C)N-^-(3,4,5-trimethoxybenzoyl)-N2-methyl-N2-( 4-trifluoromethyl-phenyl)-1,3-diaminopropan-2-ol D) N-j^- (3,4,5-trimethoxybénzoyl)-N2-methyl-N2-(4-methylphenyl)-1,3- diaminopropan-2-ol E) N1-(3,4,5-trimethoxybenzoyl)-N2~ethyl-N2-(4-fluorophenyl)-1,3-diaminopropan-2-ol F) ^-(3,4 ,5 -trimethoxybenzoyl) -n2~ (2 ,4 , 6-trimethylphenyl)-1, 3-diaminopropan-2-ol G) ^-(3,4,5-triethoxybenzoyl)-N2-methyl-N2-(4- fluorophenyl)-1,3-diaminopropan-2-ol H) N1_(4-methoxy-2,3-ethylenedioxybenzoyl)-N2~methyl-N2-(4-fluoro-phenyl)-1,3-diaminopropane-2 -beer

I) N1-(4-butoxy-3,4-dimethoxybenzoyl)-N2-methyl-N2~(4-fluorfenyl)-1,3-diaminopropan-2-ol I) N1-(4-butoxy-3,4-dimethoxybenzoyl)-N2-methyl-N2~(4-fluorophenyl)-1,3-diaminopropan-2-ol

Som standardforbindelse tjente:As a standard connection served:

S) Aluminiumfosfat i gelform.S) Aluminum phosphate in gel form.

Resultatene fremgår av den efterfølgende tabell. The results appear in the following table.

Fremgangsmåteforbindelsene viser således eri fremragende stabilisering av maveslimhuden. På grunn av deres lave toksisitet har de dessuten en god terapeutisk bredde. The process compounds thus show excellent stabilization of the gastric mucosa. Due to their low toxicity, they also have a good therapeutic breadth.

Forbindelsene med den generelle formel I og deres .salter lar seg opparbeide på kjent vis i de vanlige farmasøytiske preparat-former, f.eks. i oppløsninger, stikkpiller, tabletter, kapsler eller dragéer. Enkeltdosen utgjør for voksne ved oral administrasjon 50 til 150 mg og dagsdosen er 150 til 450 mg. The compounds with the general formula I and their salts can be prepared in a known manner in the usual pharmaceutical preparation forms, e.g. in solutions, suppositories, tablets, capsules or dragees. The single dose for adults by oral administration is 50 to 150 mg and the daily dose is 150 to 450 mg.

EksempelIExample I

Tabletter med 100 mg N^-(3,4}5-trimethoxybenzoyl)-N2~methyl-N2~(4-fluorfenyl)-1,3~diaminopropan-2-ol som virkestoff. Tablets with 100 mg N^-(3,4}5-trimethoxybenzoyl)-N2~methyl-N2~(4-fluorophenyl)-1,3~diaminopropan-2-ol as active ingredient.

1 tablett inneholder:1 tablet contains:

Fremstillingsmetode: Av gelatinet fremstilles i vann et 10%-ig slim. Virkestoff, lactose, maisstivelse og "Primojel" blandes og granuleres med det ovenfor fremstilte slim gjennom en sikt med maskevidde 1,5 mm. Granulatet tørres ved 40°C, føres igjen gjennom sikten, blandes med "Aerosil 200" og magnesium-stearat og presses til tabletter. Stempel 9 mm. Production method: A 10% slime is made from the gelatin in water. Active ingredient, lactose, cornstarch and "Primogel" are mixed and granulated with the slime prepared above through a sieve with a mesh size of 1.5 mm. The granulate is dried at 40°C, passed through the sieve again, mixed with "Aerosil 200" and magnesium stearate and pressed into tablets. Stamp 9 mm.

De efterfølgende eksempler tjener til å belyse oppfinnelsen. The following examples serve to illustrate the invention.

Eksempel 1Example 1

Til en oppløsning av 32,7 g -methyl-N -(4-fluorfenyl)-1,3-diaminopropan-2-ol og 18jl g triethylamin i 400 ml kloroform tildryppes ved værelsetemperatur under omrøring 38 g 3,4,5-trimethoxybenzoylklorid i 50 ml kloroform. Reaksjonsoppløsningen tilsettes efter 16 timer vann, derpå vaskes den fraskilte organ-iske fase med vann og tørres over natriumsulfat. Det efter filtrering og fordampning av oppløsningsmidlet i vakuum erholdte residuum krystalliseres fra aceton/petrolether. Man får 62,6 g N1~(3,4 »5-t rimethoxybenzoyl)-N2-methyl-N2~(4-fluorfenyl)-1,3" diaminopropan-2-ol med smp. 113-ll6°C. To a solution of 32.7 g of -methyl-N -(4-fluorophenyl)-1,3-diaminopropan-2-ol and 18 g of triethylamine in 400 ml of chloroform, 38 g of 3,4,5-trimethoxybenzoyl chloride are added dropwise at room temperature with stirring in 50 ml of chloroform. After 16 hours, water is added to the reaction solution, then the separated organic phase is washed with water and dried over sodium sulphate. The residue obtained after filtration and evaporation of the solvent in vacuum is crystallized from acetone/petroleum ether. 62.6 g of N1-(3,4-5-trimethoxybenzoyl)-N2-methyl-N2-(4-fluorophenyl)-1,3-diaminopropan-2-ol with mp 113-116°C are obtained.

Eksempel 2Example 2

5,1 g 3,4,5-trimethoxybenzoylklorid i 100 ml dioxan omrøres i 12 timer med 4,0 g N.-methyl-N,-(4-fluorfenyl)-1,3-diaminopropan-2-ol og 2,8 g kaliumcarbonat. Den filtrerte oppløsning inndampes i vakuum og residuet i 50 ml methanol oppvarmes med 15 ml 10%-ig natriumhydroxydoppløsning 1 time ved 6o°C. Oppløsningsmidlet avdampes i vakuum. Forbindelsen taes opp i kloroform og isoleres. Fra aceton/petrolether fåes 5,5 g krystallinsk -(3>4,5-trimethoxybenzoyl )-N2-methyl-N2-(4-fluorfenyl)-1,3-diaminopropan-2-ol med smp, 113-ll6°c. 5.1 g of 3,4,5-trimethoxybenzoyl chloride in 100 ml of dioxane is stirred for 12 hours with 4.0 g of N.-methyl-N,-(4-fluorophenyl)-1,3-diaminopropan-2-ol and 2, 8 g of potassium carbonate. The filtered solution is evaporated in vacuo and the residue in 50 ml of methanol is heated with 15 ml of 10% sodium hydroxide solution for 1 hour at 6o°C. The solvent is evaporated in vacuo. The compound is taken up in chloroform and isolated. From acetone/petroleum ether, 5.5 g of crystalline -(3>4,5-trimethoxybenzoyl)-N2-methyl-N2-(4-fluorophenyl)-1,3-diaminopropan-2-ol are obtained with mp, 113-116°C .

E ksempel 3Example 3

4,0 g -methyl - N - (4-f luorf enyl) -1, 3-diaminopropan-2-ol oppvarmes i 6 timer under tilbakeløp med 5,1 g 3,4,5-trimethoxybenzoylklorid i 100 ml benzen. Derpå blir efter tilsetning av 20 ml 20%-ig vandig natriumhydroxydoppløsning blandet godt i 4.0 g of -methyl-N-(4-fluorophenyl)-1,3-diaminopropan-2-ol is heated for 6 hours under reflux with 5.1 g of 3,4,5-trimethoxybenzoyl chloride in 100 ml of benzene. Then, after adding 20 ml of 20% aqueous sodium hydroxide solution, it is mixed well

1,5 timer ved ca. 6o°c. Efter opparbeidelse og krystallisasjon fra aceton/petrolether får man 6,0 g N]L-(3 ,4 ,5-t rimethoxybenzoyl) -N2~ methyl-N2-(4-fluorfenyl)-1,3-diaminopropan-2-ol med smp. 113-ll6°C. Eksempel 4 1.5 hours at approx. 6o°c. After work-up and crystallization from acetone/petroleum ether, 6.0 g of N]L-(3,4,5-trimethoxybenzoyl)-N2~ methyl-N2-(4-fluorophenyl)-1,3-diaminopropan-2-ol are obtained with m.p. 113-116°C. Example 4

5,3 g 3,4,5-trimethoxybenzoesyre oppløses i 40ml kloroform og 2,8 g triethylamin og tilsettes ved 0 - 5°C 3,0 g klormaursyre-ethylester. Efter 30 minutter avkjøles til -10°C, og en oppløsning Dissolve 5.3 g of 3,4,5-trimethoxybenzoic acid in 40 ml of chloroform and 2.8 g of triethylamine and add 3.0 g of chloroformic acid ethyl ester at 0 - 5°C. After 30 minutes, cool to -10°C, and a solution

av 5,0 g N1-methyl-N1-(4-fluorfenyl)-1,3-diaminopropan-2-ol i 50 ml kloroform tilsettes. Man lar temperaturen igjen stige til 0-5°C. Efter 2 timer opparbeides oppløsningen. Efter kromatografi på aluminiumoxyd av aktivitetstrinnet II med kloroform/toluen får man ved krystallisasjon fra aceton/petrolether 7,8 g ^-(3,4, 5-t rimethoxybenzoyl-N2-met hyl-N2 (4-f luorf enyl) -1, 3-diaminopropan-2-ol med smp. 113-ll6°C. of 5.0 g of N1-methyl-N1-(4-fluorophenyl)-1,3-diaminopropan-2-ol in 50 ml of chloroform is added. The temperature is allowed to rise again to 0-5°C. After 2 hours, the solution is worked up. After chromatography on aluminum oxide of the activity step II with chloroform/toluene, crystallization from acetone/petroleum ether gives 7.8 g of ^-(3,4,5-trimethoxybenzoyl-N2-methyl-N2 (4-fluorophenyl)-1 , 3-diaminopropan-2-ol with mp 113-116°C.

Eksempel 5Example 5

1,9 g N-^-methyl-N-L~ (4-f luorf enyl)-1, 3-diaminopropan-2-ol oppvarmes under tilbakeløp 1 time med 2,3 g 3,4,5-trimethoxybenzoesyre-methylester og 0,49pulverisert natriumhydroxyd i 50 ml xylen. Efter filtrering og fordampning av oppløsningsmidlet får man 2,4 g -(3,4,5-trimethoxybenzoyl)-N2~methyl-N2~(4-fluor-fenyl)-1,3-diaminopropan-2-ol. Forbindelsen krystalliserer efter filtrering over aluminiumoxyd med aktivitetstrinn II med 1.9 g of N-^-methyl-N-L~ (4-fluorophenyl)-1, 3-diaminopropan-2-ol is heated under reflux for 1 hour with 2.3 g of 3,4,5-trimethoxybenzoic acid methyl ester and 0 .49 powdered sodium hydroxide in 50 ml xylene. After filtration and evaporation of the solvent, 2.4 g of -(3,4,5-trimethoxybenzoyl)-N2~methyl-N2~(4-fluoro-phenyl)-1,3-diaminopropan-2-ol are obtained. The compound crystallizes after filtration over aluminum oxide with activity level II with

■ toluen/methylenklorid fra acetoh/petrolether med et smp. på 113-ll6°C. ■ toluene/methylene chloride from acetoh/petroleum ether with a m.p. of 113-116°C.

Eksempel 6Example 6

Tilsvarende eksemplene 1-3 får man av 4-methoxy-3,5-dibenzyloxy-benzoylklorid og -methyl-N^-(4-klorfenyl)-1,3~di-aminopropan-2-ol N-^-(4-methoxy-3,5-dibenzyloxybenzoyl) -N2~ methyl-N2-(4-klorfenyl)-1,3-diaminopropan-2-ol med smp. 155-158°C. Corresponding to examples 1-3, 4-methoxy-3,5-dibenzyloxy-benzoyl chloride and -methyl-N^-(4-chlorophenyl)-1,3~di-aminopropan-2-ol N-^-(4- methoxy-3,5-dibenzyloxybenzoyl)-N2~ methyl-N2-(4-chlorophenyl)-1,3-diaminopropan-2-ol with m.p. 155-158°C.

Eksempel 7Example 7

Omsettes under reaksjonsbetingelsene i eksempel 1 - 5 et 3,4,5-trimethoxybenzoylderivat med den generelle formel II med 1) N-fenyl-1,3-diaminopropan-2-ol Under the reaction conditions in examples 1 - 5, a 3,4,5-trimethoxybenzoyl derivative of the general formula II is reacted with 1) N-phenyl-1,3-diaminopropan-2-ol

2) N-(2-fluorfenyl)-1,3~diaminopropan-2-ol2) N-(2-fluorophenyl)-1,3-diaminopropan-2-ol

3) N-(3-fluorfenyl)-1,3-diaminopropan-2-ol3) N-(3-fluorophenyl)-1,3-diaminopropan-2-ol

4) N-(4-fluorfenyl)-1,3-diaminopropan-2-ol4) N-(4-fluorophenyl)-1,3-diaminopropan-2-ol

5) N-(2-klorfenyl)-1,3-diaminopropan-2-ol5) N-(2-chlorophenyl)-1,3-diaminopropan-2-ol

6) N-(2-raethylfenyl)-1,3-diaminopropan-2-ol6) N-(2-raethylphenyl)-1,3-diaminopropan-2-ol

7) N-(3-methylfenyl)-1,3-diaminopropan-2-ol7) N-(3-methylphenyl)-1,3-diaminopropan-2-ol

8) N-(3,4-diklorfenyl)-1,3-diaminopropan-2-ol8) N-(3,4-dichlorophenyl)-1,3-diaminopropan-2-ol

9) N-(3-klor-2-methylfenyl)-1,3-diaminopropan-2-ol9) N-(3-chloro-2-methylphenyl)-1,3-diaminopropan-2-ol

10) Nt(2 , 6-dimethylf enyl) -1, 3-diaminopropan-2-ol10) Nt(2,6-dimethylphenyl)-1,3-diaminopropan-2-ol

11) N1-methyl-N1-(4-klorfenyl)-1,3-diaminopropan-2-ol11) N1-methyl-N1-(4-chlorophenyl)-1,3-diaminopropan-2-ol

12) N-^-methyl-N.^- (4 -bromf enyl) -1, 3-diaminopropan-2-ol12) N-^-methyl-N.^-(4-bromophenyl)-1, 3-diaminopropan-2-ol

13 ) N-^-methyl-N.^ - (4-methylf enyl) -1, 3-diaminopropan-2-ol13 ) N-^-methyl-N.^- (4-methylphenyl)-1, 3-diaminopropan-2-ol

14) -methyl-N^-(4-isopropylfenyl)-1,3-diaminopropan-2-ol 14) -methyl-N^-(4-isopropylphenyl)-1,3-diaminopropan-2-ol

-methyl-N.^-(4-t rif luormethylf enyl)-1,3-diaminopropan-2-ol -methyl-N,^-(4-trifluoromethylphenyl)-1,3-diaminopropan-2-ol

16) -methyl-N.^ - (4-nit rof enyl) -1, 3-diaminopropan-2-ol16) -methyl-N.^-(4-nitrophenyl)-1,3-diaminopropan-2-ol

17) N^-methyl-N^-(3-methoxyfenyl)-1,3~diaminopropan-2-ol17) N^-methyl-N^-(3-methoxyphenyl)-1,3-diaminopropan-2-ol

18) N1-methyl-N1-(3,4-diklorfenyl)-1,3-diaminopropan-2-ol18) N1-methyl-N1-(3,4-dichlorophenyl)-1,3-diaminopropan-2-ol

19) -methyl-N^-(3,4-dimethoxyfenyl)-1,3_diaminopropan-2-ol 19) -methyl-N^-(3,4-dimethoxyphenyl)-1,3_diaminopropan-2-ol

20) N^-ethyl-N-j^-f enyl-1,3-diaminopropan-2-ol20) N^-ethyl-N-j^-phenyl-1,3-diaminopropan-2-ol

21) N^-ethyl-N.^-(4-f luorf enyl)-1, 3-diaminopropan-2-ol21) N^-ethyl-N.^-(4-fluorophenyl)-1, 3-diaminopropan-2-ol

22) -pro<py>l-N^-f en<y>l-1, 3~diaminopropan-2-ol22) -pro<py>l-N^-f en<y>l-1, 3~diaminopropan-2-ol

23) N-^propyl-N.^- (4-klorf enyl) -1, 3-diaminopropan-2-ol23) N-^propyl-N.^-(4-chlorophenyl)-1, 3-diaminopropan-2-ol

24) N-^-isopropyl-N-^-f enyl-1, 3-diaminopropan-2-ol24) N-^-isopropyl-N-^-phenyl-1, 3-diaminopropan-2-ol

25) - ((3-hydroxy et hyl) -N^ -f enyl-1, 3~diaminopropan-2-ol25) - ((3-hydroxy et hyl)-N^-phenyl-1, 3-diaminopropan-2-ol

26) - (|3-methoxyethyl)-N1- (4-klorf enyl)-1,3-diaminopropan-2-ol 26) - (|3-methoxyethyl)-N1-(4-chlorophenyl)-1,3-diaminopropan-2-ol

27) N-(2,4,6-trimethylf enyl)-1,3-diaminopropan-2-ol27) N-(2,4,6-trimethylphenyl)-1,3-diaminopropan-2-ol

28) N-j^-methyl-Ng- (4-ethylf enyl) -1, 3-diaminopropan-2-ol får man: 28) N-j^-methyl-Ng-(4-ethylphenyl)-1, 3-diaminopropan-2-ol is obtained:

Eksempel 8 Example 8

Blir under betingelsene i eksempel 1-3 Becomes under the conditions in example 1-3

1) 2,3,4-t rimethoxybenzoylklorid,1) 2,3,4-trimethoxybenzoyl chloride,

2) 2,4>5-trimethoxybenzoylklorid,2) 2,4>5-trimethoxybenzoyl chloride,

3) 3>4j5-triethoxybenzoylklorid, 3) 3>4j5-triethoxybenzoyl chloride,

4) 4-methoxy-3,5-dibenzyloxybenzoylklorid,4) 4-methoxy-3,5-dibenzyloxybenzoyl chloride,

5) 3»4»5-tribenzyloxybenzoylklorid, 5) 3»4»5-tribenzyloxybenzoyl chloride,

6) 4-acetoxy-3,5-dimethoxybenzoylklorid,6) 4-acetoxy-3,5-dimethoxybenzoyl chloride,

7) 4-ethoxycarbonyloxy-3,5-dimethoxybenzoylklorid,7) 4-ethoxycarbonyloxy-3,5-dimethoxybenzoyl chloride,

8) 2-methoxy-4,5-methylendioxybenzoylklorid,8) 2-methoxy-4,5-methylenedioxybenzoyl chloride,

9) 4-methoxy-2,3-ethylendioxybenzoylklorid,9) 4-methoxy-2,3-ethylenedioxybenzoyl chloride,

10) 4-ethoxy-2,3-ethylendioxybenzoylklorid, 10) 4-ethoxy-2,3-ethylenedioxybenzoyl chloride,

11) 3-methoxy-4,5-ethylendioxybenzoylklorid hhv.11) 3-methoxy-4,5-ethylenedioxybenzoyl chloride or

12) 3-ethoxy-4,5-ethylendioxybenzoylklorid12) 3-ethoxy-4,5-ethylenedioxybenzoyl chloride

omsatt med N.^-methyl-(4-fluorfenyl)-1,3-diaminopropan-2-ol, får man: reacted with N,^-methyl-(4-fluorophenyl)-1,3-diaminopropan-2-ol, one obtains:

Eksempel 9 Example 9

2,1 g 2-methoxy-4,5-methylendioxybenzoesyre-ethylester oppvarmes i 2 timer med 130°C under nitrogen med 9,39N.^-methyl-N.^-(4-f luorf enyl) -1,3-diaminopropan-2-ol og 0,49pulverisert natriumhydroxyd. Reaksjonsblandingen taes opp i kloroform, uopp-løst materiale frafiltreres, og filtratet kromatograferes på aluminiumoxyd med aktivitetstrinn II med kloroform. Man får 1,2 g N^-(2-methoxy-4,5-methylendioxybenzoyl)-TNL,-methyl-N2~(4-fluor-f enyl)-1, 3~diaminopropan-;2-ol som en olje. 2.1 g of 2-methoxy-4,5-methylenedioxybenzoic acid ethyl ester is heated for 2 hours at 130°C under nitrogen with 9,39N.^-methyl-N.^-(4-fluorophenyl)-1,3- diaminopropan-2-ol and 0.49 powdered sodium hydroxide. The reaction mixture is taken up in chloroform, undissolved material is filtered off, and the filtrate is chromatographed on aluminum oxide with activity level II with chloroform. 1.2 g of N^-(2-methoxy-4,5-methylenedioxybenzoyl)-TNL,-methyl-N2~(4-fluoro-phenyl)-1,3~diaminopropan-;2-ol are obtained as an oil .

IR-spektrum (olje) cm"<1>: 3380 (NH/OH); l64o (NC=0).IR spectrum (oil) cm"<1>: 3380 (NH/OH); 1640 (NC=0).

Eksempel 10Example 10

1,99N1-(3,4,5-trimethoxybenzoyl)-N2-(4-fluorfenyl)-l,3-diaminopropan-2-ol oppvarmes i 3 timer på vannbad med 7,6 ml maur-syre og 2 ml 36%-ig vandig formalinoppløsning. Den derpå med is tilsatte reaksjonsoppløsning gjøres så alkalisk med fortynnet natriumhydroxydoppløsning, og forbindelsen isoleres fra kloroform. Efter kromatografi på aluminiumoxyd med aktivitetstrinn II med methylenklorid/kloroform fåes efter omkrystallisasjon fra aceton/petrolether 1,1 g N^-(3,4,5-trimethoxybenzoyl)-N2~methyl-N2-(4-fluorfenyl)-1,3-diaminopropan-2-ol med smp. 113-ll6°C. 1,99N1-(3,4,5-trimethoxybenzoyl)-N2-(4-fluorophenyl)-1,3-diaminopropan-2-ol is heated for 3 hours on a water bath with 7.6 ml of formic acid and 2 ml of 36% -ig aqueous formalin solution. The reaction solution, which is then added with ice, is then made alkaline with dilute sodium hydroxide solution, and the compound is isolated from chloroform. After chromatography on aluminum oxide with activity level II with methylene chloride/chloroform, after recrystallization from acetone/petroleum ether, 1.1 g of N^-(3,4,5-trimethoxybenzoyl)-N2~methyl-N2-(4-fluorophenyl)-1,3 -diaminopropan-2-ol with m.p. 113-116°C.

Eksempel 11Example 11

1,9 g N-L~( 3,4 ,5-trimethoxybenzoyl) -N2~ (4-f luorf enyl) -1,3-diaminopropan-2-ol oppløses i 30 ml dioxan, tilsettes 1,5 g nat-riumbicarbonat i 2,5 ml vann og oppvarmes i 1 time ved 6o°C efter tilsetning av 1,6 ml dimethylsulfat. Oppløsningen omrøres derpå med 10 ml 15%-ig nat riumhydroxydoppløsning, oppløsningsmidlet avdrives i vakuum, og forbindelsen isoleres fra kloroform. Man får Dissolve 1.9 g of N-L~(3,4,5-trimethoxybenzoyl)-N2~(4-fluorophenyl)-1,3-diaminopropan-2-ol in 30 ml of dioxane, add 1.5 g of sodium bicarbonate in 2.5 ml of water and heated for 1 hour at 6o°C after adding 1.6 ml of dimethylsulphate. The solution is then stirred with 10 ml of 15% sodium hydroxide solution, the solvent is driven off in vacuo, and the compound is isolated from chloroform. You get

1,2 g N1-(3,4,5-trimethoxybenzoyl)-N2-inGthyl-N2-(4-fluorfenyl)-1,3-diaminopropan-2-ol. Forbindelsen krystalliserer fra aceton/petrolether med et smp. på 113-ll6°C. 1.2 g of N1-(3,4,5-trimethoxybenzoyl)-N2-ynGethyl-N2-(4-fluorophenyl)-1,3-diaminopropan-2-ol. The compound crystallizes from acetone/petroleum ether with a m.p. of 113-116°C.

Eksempel 12Example 12

3,6 g N1-(3,4,5-trimethoxybenzoyl)-N2~fenyl-1,3-diamino-propan-2-ol oppløses i 6o ml dioxan og tilsettes 3,0 g natrium-bicarbonat i 6 ml vann. Efter tilsetning av 4,4 ml diethylsulfat oppvarmes i 0,5 timer ved 6o°C. Derpå tilsettes 5 ml 15%-ig natriumhydroxydoppløsning, oppløsningsmidlet avdrives i vakuum, og forbindelsen isoleres fra kloroform. Efter kromatografi på aluminiumoxyd med aktivitetstrinn II med methylenklorid, fåes 2,5 g N^-(3,4,5-t rimethoxybenzoyl)-N2~ethyl-N2-fenyl-1,3-diamino-propan-2-ol. Den fra isopropanol krystalliserte forbindelse smelter ved ll4-H5°C. 3.6 g of N1-(3,4,5-trimethoxybenzoyl)-N2~phenyl-1,3-diamino-propan-2-ol are dissolved in 60 ml of dioxane and 3.0 g of sodium bicarbonate in 6 ml of water are added. After adding 4.4 ml of diethyl sulphate, heat for 0.5 hours at 6o°C. 5 ml of 15% sodium hydroxide solution is then added, the solvent is removed in vacuo, and the compound is isolated from chloroform. After chromatography on aluminum oxide with activity stage II with methylene chloride, 2.5 g of N^-(3,4,5-trimethoxybenzoyl)-N2-ethyl-N2-phenyl-1,3-diamino-propan-2-ol are obtained. The compound crystallized from isopropanol melts at 114-H5°C.

Eksempel 13Example 13

24,8 g ^-(3,4,5-tribenzyloxybenzoyl)-N2-methyl-N2-(4-fluorfenyl)-1,3-diaminopropan-2-ol oppløses i 1000 ml methanol og hydrogeneres ved normaltrykk i nærvær av 2 g 5%-ig palladium- 24.8 g of ^-(3,4,5-tribenzyloxybenzoyl)-N2-methyl-N2-(4-fluorophenyl)-1,3-diaminopropan-2-ol are dissolved in 1000 ml of methanol and hydrogenated at normal pressure in the presence of 2 g 5% palladium

kull. Efter fraskillelse av katalysatoren og oppløsningsmidlet får man ved krystallisasjon fra ethylacetat/petrolether 13 g N.^-(3,4,5-trihydroxybenzoyl)-N2-methyl-N2-(4-fluorfenyl)-1,3-diamino-propan-2-ol med smp. l67-l69°C. coal. After separation of the catalyst and the solvent, crystallization from ethyl acetate/petroleum ether yields 13 g of N,^-(3,4,5-trihydroxybenzoyl)-N2-methyl-N2-(4-fluorophenyl)-1,3-diamino-propane- 2-ol with m.p. 167-169°C.

Tilsvarende fåes av 10,5 g N-(4-methoxy-3,5-dibenzyloxybenzoyl)-N2~methyl-N2~(4-fluorfenyl)-1,3-diaminopropan-2-ol, Similarly, from 10.5 g of N-(4-methoxy-3,5-dibenzyloxybenzoyl)-N2~methyl-N2~(4-fluorophenyl)-1,3-diaminopropan-2-ol,

6,3 g Nx-(4-methoxy-3,5-dihydroxybenzoyl)-N2-methyl-N2~(4-fluor-fenyl)-1,3-diaminopropan-2-ol med smp. 170-172°C, hhv. av Nx- (4-methoxy-3 ,5-dibenzyloxybenzoyl) -N2-methyl -N2~(4-klorf enyl) - 1,3-diaminopropan-2-ol, 1^-(4-methoxy-3,5-dihydroxybenzoyl)-N2"methyl-N2-(4-klorfenyl)-1,3-diaminopropan-2-ol som olje. 6.3 g of Nx-(4-methoxy-3,5-dihydroxybenzoyl)-N2-methyl-N2~(4-fluoro-phenyl)-1,3-diaminopropan-2-ol with m.p. 170-172°C, resp. of Nx-(4-methoxy-3,5-dibenzyloxybenzoyl)-N2-methyl -N2~(4-chlorophenyl)-1,3-diaminopropan-2-ol, 1^-(4-methoxy-3,5- dihydroxybenzoyl)-N2"methyl-N2-(4-chlorophenyl)-1,3-diaminopropan-2-ol as an oil.

IR (olje) cm"<1>: 3200-3400 (NH/OH); 1625 (NC=0).IR (oil) cm"<1>: 3200-3400 (NH/OH); 1625 (NC=0).

Eksempel 14Example 14

77 g N1-(3,5-dimethoxy-4-acetoxybenzoyl)-N2-methyl-N2-(4-fluorfenyl)-1,3-diaminopropan-2-ol opplø ses i 400 ml aceton og Dissolve 77 g of N1-(3,5-dimethoxy-4-acetoxybenzoyl)-N2-methyl-N2-(4-fluorophenyl)-1,3-diaminopropan-2-ol in 400 ml of acetone and

behandles ved 50°C med 8,4 g natriumhydroxyd i 300 ml vann. Oppløs-ningen surgjøres med fortynnet saltsyre, oppløsningsmidlet avdrives i vakuum, og det utfelte stoff frafiltreres. Man får ved krystalli- treated at 50°C with 8.4 g of sodium hydroxide in 300 ml of water. The solution is acidified with dilute hydrochloric acid, the solvent is removed under vacuum, and the precipitated substance is filtered off. One obtains by crystallization

sasjon fra isopropanol 55 g 1^-(3,5-dimethoxy-4-hydroxybenzoyl)-N2-methyl-N2-(4-fluorfenyl)-1,3-diaminopropan-2-ol med smp. l6l-l64°C. Hydrokloridet smelter ved 220-223°C. sation from isopropanol 55 g 1^-(3,5-dimethoxy-4-hydroxybenzoyl)-N2-methyl-N2-(4-fluorophenyl)-1,3-diaminopropan-2-ol with m.p. 161-164°C. The hydrochloride melts at 220-223°C.

Eksempel 15Example 15

På tilsvarende måte får man av 2 g ^-(3,5-dimethoxy-4-ethoxycarbonyloxybenzoyl)-N2-methyl-N2~(4-fluorfenyl)-1,3-diamino-propan-2-ol med 5 ml vandig ammoniakkoppløsning i 50 ml methanol In a similar manner, 2 g of ^-(3,5-dimethoxy-4-ethoxycarbonyloxybenzoyl)-N2-methyl-N2~(4-fluorophenyl)-1,3-diamino-propan-2-ol is obtained with 5 ml of aqueous ammonia solution in 50 ml of methanol

ved 70°C i 2 timer N1-(3,5-dimethoxy-4-hydroxybenzoyl)-N2-methyl-N2~(4-fluorfenyl)-1,3-diaminopropan-2-ol. Den fra isopropanol krystalliserte forbindelse smeltet ved l6l-l64 C. at 70°C for 2 hours N1-(3,5-dimethoxy-4-hydroxybenzoyl)-N2-methyl-N2~(4-fluorophenyl)-1,3-diaminopropan-2-ol. The compound crystallized from isopropanol melted at 161-164 C.

Eksempel 16Example 16

3,8 g N1-(4-hydroxy-3,5-dimethoxybenzoyl)-N2-methyl-N2-(4-fluorfenyl)-1,3~diaminopropan-2-ol oppvarmes i 16 timer under tilbakeløp med den ekvivalente mengde nat riummethylat (0,23 g natrium i 50 ml methanol) med 6,0 g n-but ylbromid. Reaksjons - produktet isoleres fra kloroform efter fordampning av oppløsnings-midlet i vakuum og renses ved filtrering over aluminiumoxyd med aktivitetstrinn II med kloroform. Man får 2,4 g fra ether/petroi-ether krystallisert -(4-butoxy-3,5-dimethoxybenzoyl)-N2~methyl-<N>2~(4-fluorfenyl)-1,3-diaminopropan-2-ol med smp. 87-90°C. 3.8 g of N1-(4-hydroxy-3,5-dimethoxybenzoyl)-N2-methyl-N2-(4-fluorophenyl)-1,3~diaminopropan-2-ol are heated for 16 hours under reflux with the equivalent amount of rium methylate (0.23 g sodium in 50 ml methanol) with 6.0 g n-butyl bromide. The reaction product is isolated from chloroform after evaporation of the solvent in vacuum and purified by filtration over aluminum oxide with activity level II with chloroform. 2.4 g of crystallized -(4-butoxy-3,5-dimethoxybenzoyl)-N2~methyl-<N>2~(4-fluorophenyl)-1,3-diaminopropan-2-ol are obtained from ether/petroi-ether with m.p. 87-90°C.

På tilsvarende måte får man fra N^-(4~hydroxy-3,5-dimethoxy-benzoyl)-N2-methyl-N2~(4-fluorfenyl)-1,3-diaminopropan-2-ol og den ekvivalente mengde allylbromid, propargylbromid eller 4-klorbenzyl-klorid forbindelsene N^-(4-allyloxy~3,5-dimethoxybenzoyl)-N2~methyl-N2-(4-fluorfenyl)-1,3-diaminopropan-2-ol med smp. 100-103°C, N^-(4-propargyloxy-3,5-dimethoxybenzoyl)-N2-methyl-N2~(4-fluorfenyl)-1,3-diaminopropan-2-ol med smp. 135-138°C og N -[4-(4-klorbenzyloxy)-3,5-dimethoxybenzoyl]-Ng-methyl-N2-(4-fluorfenyl)-1,3-diamino-propan-2-ol med smp. l40-l44 C. In a similar way, one obtains from N^-(4~hydroxy-3,5-dimethoxy-benzoyl)-N2-methyl-N2~(4-fluorophenyl)-1,3-diaminopropan-2-ol and the equivalent amount of allyl bromide, propargyl bromide or 4-chlorobenzyl chloride the compounds N^-(4-allyloxy~3,5-dimethoxybenzoyl)-N2~methyl-N2-(4-fluorophenyl)-1,3-diaminopropan-2-ol with m.p. 100-103°C, N^-(4-propargyloxy-3,5-dimethoxybenzoyl)-N2-methyl-N2~(4-fluorophenyl)-1,3-diaminopropan-2-ol with m.p. 135-138°C and N -[4-(4-chlorobenzyloxy)-3,5-dimethoxybenzoyl]-Ng-methyl-N2-(4-fluorophenyl)-1,3-diamino-propan-2-ol with m.p. l40-l44 C.

Fra N1-(4-hydroxy-3,5-dimethoxybenzoyl)-N2-methyl-N2-(4-fluorfenyl)-l,3-diaminopropan-2-ol og den ekvivalente mengde natriummethylat i methanol og overskudd av isopropylbromid fåes i autoklav ved 90-95°C ^-(4-isopropoxy-3,5-dimethoxybenzoyl)-N2-methyl-N2-(4-fluorfenyl)-1,3-diaminopropan-2-ol med smp. 122-125°C. From N1-(4-hydroxy-3,5-dimethoxybenzoyl)-N2-methyl-N2-(4-fluorophenyl)-1,3-diaminopropan-2-ol and the equivalent amount of sodium methylate in methanol and an excess of isopropyl bromide is obtained in an autoclave at 90-95°C ^-(4-isopropoxy-3,5-dimethoxybenzoyl)-N2-methyl-N2-(4-fluorophenyl)-1,3-diaminopropan-2-ol with m.p. 122-125°C.

Eksempel 17Example 17

Til 0,12 g natrium i 50 ml methanol tilsettes 1,99N^-(4-hydroxy-3,5-dimethox<y>benzo<y>l)-Ng-meth<y>l-Ng-(4-fluorfen<y>l) -1,3-diaminopropan-2-ol, og oppløsningen oppvarmes under tilbakeløp i 30 minutter. Det efter avdampning av oppløsningsmidlet gjenvær-ende residuum krystalliserer fra isopropanol. Natrium-[N^-(4-oxydo-3,5-dimethoxybenzoyl)-Ng-methyl-Ng-(4-fluorfenyl)-1,3-diaminopropan-2-ol] smelter over 250°C. To 0.12 g sodium in 50 ml methanol is added 1.99N^-(4-hydroxy-3,5-dimethox<y>benzo<y>l)-Ng-meth<y>l-Ng-(4-fluorophen <y>l)-1,3-diaminopropan-2-ol, and the solution is heated under reflux for 30 minutes. The residue remaining after evaporation of the solvent crystallizes from isopropanol. Sodium-[N^-(4-oxydo-3,5-dimethoxybenzoyl)-Ng-methyl-Ng-(4-fluorophenyl)-1,3-diaminopropan-2-ol] melts above 250°C.

Eksempel 18Example 18

Til en oppløsning av 0,0799magnesium i 50 ml methanol tilsettes en oppløsning av 2,46 g N^-(4-hydroxy-3,5-dimethoxy-benzoyl )-Ng-methyl-Ng-(4-fluorfenyl)-1,3-diaminopropan-2-ol i 50 ml methanol og 0,12 ml vann. Efter 2 timers oppvarmning ved 65°C får man hydroxy-magnesium-[N^-(4-oxydo-3,5-dimethoxybenzoyl)-Ng-methyl-Ng-(4-f luorf enyl)-1, 3~diaminopropan-2-ol] med smp. over 250°C. To a solution of 0.0799 magnesium in 50 ml of methanol is added a solution of 2.46 g of N^-(4-hydroxy-3,5-dimethoxy-benzoyl)-Ng-methyl-Ng-(4-fluorophenyl)-1, 3-diaminopropan-2-ol in 50 ml of methanol and 0.12 ml of water. After heating for 2 hours at 65°C, hydroxy-magnesium-[N^-(4-oxydo-3,5-dimethoxybenzoyl)-Ng-methyl-Ng-(4-fluorophenyl)-1, 3-diaminopropan- 2-ol] with m.p. above 250°C.

Eksempel 19Example 19

1,39N^-(4-hydroxy-3,5-dimethoxybenzoyl)-Ng-methyl-Ng-(4-fluorfenyl)-1,3-diaminopropan-2-ol suspenderes i 50 ml vann. 1,39 N -(4-hydroxy-3,5-dimethoxybenzoyl)-Ng-methyl-Ng-(4-fluorophenyl)-1,3-diaminopropan-2-ol is suspended in 50 ml of water.

Efter tilsetning av fortynnet vandig natriumhydroxydoppløsningAfter addition of dilute aqueous sodium hydroxide solution

inntil fullstendig oppløsning tilsettes en oppløsning av 0,89kobber(II)-sulfat-pentahydrat i 20 ml vann, og reaksjonsoppløs-ningen hensettes i 3 timer ved værelsetemperatur. Man får 1,5 g hydroxy-kobber(II)-[N^-(4-oxydo-3,5-dimethoxybenzoyl)-Ng-methyl-Ng-(4-fluorfenyl)-1,3-diaminopropan-2-ol] med smp. over 250°C. until complete dissolution, a solution of 0.89 copper(II) sulfate pentahydrate in 20 ml of water is added, and the reaction solution is left for 3 hours at room temperature. 1.5 g of hydroxy-copper(II)-[N^-(4-oxydo-3,5-dimethoxybenzoyl)-Ng-methyl-Ng-(4-fluorophenyl)-1,3-diaminopropan-2-ol are obtained ] with m.p. above 250°C.

På tilsvarende måte fåes med zink(II)-sulfat-heptahydrat hydroxy-zink-[N1-(4-oxydo-3,5-dimethoxybenzoyl)-Ng-methyl-Ng-(4-fluorfenyl)-1,3-diaminopropan-2-ol] med smp. over 200°C. In a similar way, with zinc(II)-sulfate heptahydrate, hydroxy-zinc-[N1-(4-oxydo-3,5-dimethoxybenzoyl)-Ng-methyl-Ng-(4-fluorophenyl)-1,3-diaminopropane- 2-ol] with m.p. above 200°C.

Eksempel 2QExample 2Q

2,3 g basisk vismut(III)-nitrat og 4,0 g Nx-(3,4,5-tri-hydroxybenzoyl)-Ng-methyl-Ng-(4-fluorfenyl)-1,3-diaminopropan-2- 2.3 g of basic bismuth(III) nitrate and 4.0 g of Nx-(3,4,5-tri-hydroxybenzoyl)-Ng-methyl-Ng-(4-fluorophenyl)-1,3-diaminopropane-2-

01 i en blanding av 50 ml eddiksyre og 50 ml vann oppvarmes i 2 timer ved 65°C . Man får 3,8 g hydroxy-vismut (III)-[^ - (3 ,4-dioxydo-5-hydroxybenzoyl)-Ng-methyl-Ng-(4-fluorfenyl)-1,3-diamino-propan-2-ol] med smp, over 200°C. 01 in a mixture of 50 ml acetic acid and 50 ml water is heated for 2 hours at 65°C. 3.8 g of hydroxybismuth (III)-[^-(3,4-dioxydo-5-hydroxybenzoyl)-Ng-methyl-Ng-(4-fluorophenyl)-1,3-diamino-propane-2- ol] with mp, above 200°C.

Pa tilsvarende måte fåes med aluminiumklorid-hexahydrat hydroxy-aluminium-[N^-(3,4-dioxydo-5-hydroxybenzoyl)-Ng-methyl-Ng-(4-f luorf enyl) -1, 3-diaminopropan-2-olJ med smp. over 200°C. In a similar way, hydroxy-aluminum-[N^-(3,4-dioxydo-5-hydroxybenzoyl)-Ng-methyl-Ng-(4-fluorenyl)-1, 3-diaminopropan-2- olJ with m.p. above 200°C.

Claims (6)

1. Analogifremgangsmåte ved fremstilling av terapeutisk aktive N -benzoyl-N„-fenyl-1,3-diaminopropan-2-oler med formelen:1. Analogous method in the preparation of therapeutically active N -benzoyl-N„-phenyl-1,3-diaminopropan-2-ols with the formula: 12 12 hvor R , R_ og R er like eller forskjellige, og er hydroxy, benzyloxy, klorbenzyloxy eller alkoxy med 1-4 carbonatomer, idet to nabogrupper kan danne en methylendioxy- eller ethylendioxy-gruppe, eller idet to methoxygrupper kan være kombinert med en allyloxy-, propargyloxy-, acetoxy- eller alkoxycarbonyloxy-gruppe- i hvilke alkoxygruppen maksimalt kan ha 2 carbonatomer, R^ er hydrogen, alkyl med 1-4 carbonatomer, (3-hydroxyethyl eller (3-methoxyethyl, R^, R^ og Ry, som er liké eller forskjellige, er hydrogen eller halogen, alkyl med 1-4 carbonatomer, alkoxy med 1-4 carbonatomer, idet to nabogrupper kan danne en methylendioxy- eller ethylendioxy-gruppe, eller en av gruppene R^ , R^ og R^ er en tri-fluormethyl- eller en nitro-gruppe, eller når R^ , Rg og R^ sammen er 3?4 ,5-trimethoxy og R^ er methyl, kan ikke mere enn to av gruppene R^, R^ og R^ være hydrogen, og deres syreaddisjonssalter, eller når i forbindelsen med den generelle formel I minst én av substituentene R^ , R^ og R^ er hydroxy, salter av disse forbindelser med farmakologisk godtagbare kationer, karakterisert ved ata) en 1,3-diaminopropan-2-ol med formelen: where R , R_ and R are the same or different, and are hydroxy, benzyloxy, chlorobenzyloxy or alkoxy with 1-4 carbon atoms, since two neighboring groups can form a methylenedioxy or ethylenedioxy group, or since two methoxy groups can be combined with an allyloxy , propargyloxy-, acetoxy- or alkoxycarbonyloxy group- in which the alkoxy group can have a maximum of 2 carbon atoms, R^ is hydrogen, alkyl with 1-4 carbon atoms, (3-hydroxyethyl or (3-methoxyethyl, R^, R^ and Ry, which are the same or different, are hydrogen or halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, two neighboring groups can form a methylenedioxy or ethylenedioxy group, or one of the groups R^ , R^ and R^ are a trifluoromethyl or a nitro group, or when R^ , Rg and R^ together are 3,4,5-trimethoxy and R^ is methyl, no more than two of the groups R^, R^ and R^ can be hydrogen, and their acid addition salts, or when in the compound with the general formula I at least one of the substituents R^ , R^ and R^ is hydroxy, salts of these compounds with pharmacologically acceptable cations, characterized by ata) a 1,3-diaminopropan-2-ol with the formula: hvor R, , R-, R,- og R„ er som ovenfor angitt, omsettes med et 4 5 6 ^7 benzoylderivat med formelen: where R, , R-, R,- and R„ are as indicated above, react with a 4 5 6 ^7 benzoyl derivative with the formula: hvor R *, R ' og R * er forethrede og/eller forestrede hydroxy-1^3 grupper som ovenfor angitt, og X er en reaksjonsdyktig syregruppe, som halogen, lavere alkoxy eller 0-CO-Y, hvor Y er lavere alkoxy, eventuelt i et inert oppløsningsmiddel ved temperaturer mellom -10°C og kokepunktet for det anvendte oppløsningsmiddel ved normaltrykk eller ved forhøyet trykk, under dannelse av en forbindelse med formel I hvor R,, R0 og R0 er forethrede og/eller forestrede hydroxygrupper som ovenfor angitt, og R^ , R^ , R^ og Ry er som ovenfor angitt, f b) én eller flere av substituentene R.., R„ og R0 med betyd- , J-evefituelt-J \ ningen benzyloxy eller klorbenzyloxy spaltes/hydrogenolytisk til de tilsvarende hydroxygrupper, c) forbindelser hvor substituentene R.., R0 eller R_ er acetoxy eller alkoxycarbonyloxy eventuelt overføres ved alkalisk hydrolyse til de tilsvarende hydroxyforbindelser, d) én eller flere av substituentene R^ , R2 og R^ med betydningen hydroxy eventuelt overføres til de ønskede alkoxy-, allyloxy-, propargyloxy- eller til den eventuelt substituerte i benzyloxygruppe med ovenstående betydning, e) R^ når den er hydrogen, eventuelt overføres til alkyl, f) de isolerte, frie baser av forbindelsene med formel I over-føres til deres syreaddis jpnssalt er, eller de frie baser frigjøres fra deres syreaddisjonssalter, eller g) forbindelsene med formel I eventuelt omsettes med farmakologisk godtagbare kationer til de tilsvarende metall-oxydoforbindelser, når minst én av substituentene R 1 R ^ og R3. er hydroxy.where R *, R ' and R * are etherified and/or esterified hydroxy-1^3 groups as indicated above, and X is a reactive acid group, such as halogen, lower alkoxy or 0-CO-Y, where Y is lower alkoxy, possibly in an inert solvent at temperatures between -10°C and the boiling point of the solvent used at normal pressure or at elevated pressure, forming a compound of formula I where R,, R0 and R0 are etherified and/or esterified hydroxy groups as indicated above, and R^, R^, R^ and Ry are as indicated above, f b) one or more of the substituents R..., R„ and R0 meaning , the J-evefituel-J \ ningen benzyloxy or chlorobenzyloxy is split/hydrogenolytically into the corresponding hydroxy groups, c) compounds where the substituents R..., R0 or R_ are acetoxy or alkoxycarbonyloxy are optionally transferred by alkaline hydrolysis to the corresponding hydroxy compounds, d) one or more of the substituents R 1 , R 2 and R 2 with the meaning hydroxy is optionally transferred to the desired alkoxy-, allyloxy-, propargyloxy- or to the optionally substituted benzyloxy group with the above meaning, e) R^ when it is hydrogen, optionally transferred to alkyl, f) the isolated free bases of the compounds of formula I are transferred to their acid addition salts, or the free bases are liberated from their acid addition salts, or g) the compounds of formula I are optionally reacted with pharmacologically acceptable cations to the corresponding metal-oxydo compounds, when at least one of the substituents R 1 R 1 and R 3 . is hydroxy. 2. Fremgangsmåte ifølge krav 1, karakterisert ved at man omsetter 1,3-diamino-propan-2-olen med formel II med et benzoylderivat med formel III i nærvær av et syrebindende middel, nemlig kaliumcarbonat, natrium-■carbonat , nat r iumhydroxyd, kaliumhydroxyd , triethylamin eller pyridin, og eventuelt anvender det i overskudd anvendte tertiære amin som oppløsningsmiddel.2. Method according to claim 1, characterized in that the 1,3-diamino-propan-2-ol of formula II is reacted with a benzoyl derivative of formula III in the presence of an acid-binding agent, namely potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or pyridine, and optionally uses the tertiary amine used in excess as a solvent. 3. Fremgangsmåte ifølge krav 1, karakterisert ved at den hydrogenolytiske avspaltning av benzyloxygruppen med hydrogen utføres i nærvær av en edelmetallkatalysator.3. Method according to claim 1, characterized in that the hydrogenolytic cleavage of the benzyloxy group with hydrogen is carried out in the presence of a noble metal catalyst. 4. Fremgangsmåte ifølge krav 3> karakterisert ved at der som edelmetallkatalysator anvendes palladiumkull, og at omsetningen utføres mellom 15° og 50°C i et inert oppløsningsmiddel.4. Method according to claim 3> characterized in that palladium charcoal is used as a noble metal catalyst, and that the reaction is carried out between 15° and 50°C in an inert solvent. 5. Fremgangsmåte ifølge krav 1, karakterisert ved at den alkaliske hydrolyse av acetoxy- eller alkoxycarbonyloxy-gruppene utføres i et inert oppløsningsmiddel mellom 25° og 80°C i en inert gassatmosfære.5. Method according to claim 1, characterized in that the alkaline hydrolysis of the acetoxy or alkoxycarbonyloxy groups is carried out in an inert solvent between 25° and 80°C in an inert gas atmosphere. 6. Fremgangsmåte ifølge krav 1, karakterisert<*> ved at man for innføring av ethergrupper på benzoylringen omsetter et alkalisalt av N^ -hydroxy-benzoylforbindelsene med et halogenalkan, halogenalken, halogenalkyn eller halogenbenzyl i nærvær av et inert oppløsningsmiddel under en inert gassatmosfære.6. Method according to claim 1, characterized<*> in that, for the introduction of ether groups on the benzoyl ring, an alkali salt of the N^ -hydroxy-benzoyl compounds is reacted with a haloalkane, haloalkene, haloalkyne or halobenzyl in the presence of an inert solvent under an inert gas atmosphere.
NO792105A 1978-06-24 1979-06-22 PROCEDURES FOR THE PREPARATION OF N1-BENZOYL-N2-PHENYL-1,3-DIAMINOPROPAN-2-OLES NO792105L (en)

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